Additional Tumor Sites Research Articles

Позитронная эмиссионная томография в диагностике и мониторинге лимфопролиферативных заболеваний

Currently, 18F FDG-PET and 18F FDG-PET/CT are widely used for diagnosis and monitoring of lymphomas. The majority of aggressive lymphomas are characterized by high glycolytic activity, which enables the visualization by using 18F FDG-PET/CT. The use of PET/CT makes it possible to clarify the stage of the disease in 10–30 % of patients, with additional tumor sites typical for advanced stage of lymphomas, which in turn effects on treatment and disease prognosis. The 18F FDG-PET/CT has the advantage over other methods of radiation diagnosis in detecting bone marrow lesions in patients with lymphomas. It has been shown that 18F FDG-PET/CT performed at early stages of chemotherapy allows differentiating patients with favorable lymphoma, which is sufficient for standard therapy and high-risk patients who require more intensive treatment with high-dose regimens of chemotherapy. After completion of therapy over 60 % of patients with HL and 40 % with aggressive non-Hodgkin’s lymphomas, have residual masses containing necrotic and/or fibrotic tissue and residual neoplastic cells. 18F FDG-PET and 18F FDG-PET/CT has been shown to be useful in identifying residual masses in 30–64 % of patients, by demonstration of persistent metabolic activity on FDG-PET. Between 62–100 % of patients with residual FDG-positive masses have been shown to relapse after first-line chemotherapy. Identification of patients with partial response to chemotherapy indicates the need for continued treatment. New radiopharmaceuticals for the diagnosis of lymphoma and evaluation of therapy effectiveness are developed. Such promising radiopharmaceuticals are 18F fluorothymidine, a biomarker of cellular proliferation and Ga-68 CXCR4, a chemokine receptor imaging biomarker.

Abstract 2138: Tumor treatment fields downregulate the BRCA1/FA pathway genes leading to reduced DNA repair capacity, the inhibition of mitophagy and enhanced cell death

Abstract The application of new physical cancer treatment modality utilizing alternating electric fields termed tumor treatment fields (TTFields) has revolutionized the treatment of recurrent and newly diagnosed glioblastoma. This non-invasive exposure to low-intensity, intermediate frequency, alternating electric fields to the region of the tumor has resulted in a significant increase in overall survival when compared to standard therapy with very minimal side effects. Clinical trials are recruiting or ongoing at additional tumor sites including lung, pancreatic, and ovarian cancer. The primary mechanism of TTField cell killing is thought to be the disruption of mitosis; however, other potential mechanisms are under investigation. Using a panel of five NSCLC cell lines we found that TTFields treatment alone inhibits cell proliferation, and decreases survival, though the degree of inhibition varies between cell lines. To understand the molecular mechanisms underlying the biological effects of TTField exposure we studied temporal gene expression changes in the NSCLC cell lines after TTField treatment. We observed that most differentially expressed genes are part of cell cycle and proliferation pathways which is in agreement with earlier findings. Interestingly we found that the expression of BRCA1 DNA damage repair pathway genes were significantly downregulated (P < 0.05) upon TTField treatment. We confirmed the downregulation of BRCA1/FA pathway proteins by western blot. When examining the nuclear role of the BRCA1/FA pathway genes we found that TTField treatment slowed the repair of ionizing radiation-induced DNA damage compared to radiation alone which is evident by an increased number of DNA double strand break repair foci at any given time. Moreover, we found that TTField treatment increased the incidence of chromatid aberrations. We also examined the newly identified BRCA1/FA pathway genes cytosolic role in mitophagy where we observed alterations in mitophagy related gene (PINK1, OSCP1, ATP5 and DAPIT) expression and confirmed the same at the protein level by western blot. We hypothesized that TTFields disrupt the clearance of damaged mitochondria due to the downregulation of BRCA1/FA pathway players, causing an imbalance in oxygen metabolism leading to the production of high levels of radical oxygen species (ROS) and as a result, cell death. Using CellROX dye we found that TTField treatment did result in increased ROS production suggesting a new mechanism of action for TTField exposure. Novel chemotherapy agents, particularly PARP inhibitors, in combination with DNA damaging agents like radiation and TTFields may be advantageous through the conditional vulnerability of down-regulated BRCA1. Citation Format: Narasimha Kumar Karanam, Lianghao Ding, Brock Sishc, Debabrata Saha, Michael D. Story. Tumor treatment fields downregulate the BRCA1/FA pathway genes leading to reduced DNA repair capacity, the inhibition of mitophagy and enhanced cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2138. doi:10.1158/1538-7445.AM2017-2138

Optimal gross tumor volume definition in lung-sparing intensity modulated radiotherapy for pleural mesothelioma: an in silico study

Background: The gross tumor volume (GTV) definition for malignant pleural mesothelioma (MPM) is ill-defined. We therefore investigated which imaging modality is optimal: computed tomography (CT) with intravenous contrast (IVC), positron emission tomography-CT (PET/CT) or magnetic resonance imaging (MRI).Material and methods: Sixteen consecutive patients with untreated stage I–IV MPM were included. Patients with prior pleurodesis were excluded. CT with IVC, 18FDG-PET/CT and MRI (T2 and contrast-enhanced T1) were obtained. CT was rigidly co-registered with PET/CT and with MRI. Three sets of pleural GTVs were defined: GTVCT, GTVCT+PET/CT and GTVCT+MRI. Quantitative and qualitative evaluations of the contoured GTVs were performed.Results: Compared to CT-based GTV definition, PET/CT identified additional tumor sites (defined as either separate nodules or greater extent of a known tumor) in 12/16 patients. Compared to either CT or PET/CT, MRI identified additional tumor sites in 15/16 patients (p = .7). The mean GTVCT, GTVCT+PET/CT and GTVCT+MRI [±standard deviation (SD)] were 630.1 cm3 (±302.81), 640.23 cm3 (±302.83) and 660.8 cm3 (±290.8), respectively. Differences in mean volumes were not significant. The mean Jaccard Index was significantly lower in MRI-based contours versus all the others.Conclusion: As MRI identified additional pleural disease sites in the majority of patients, it may play a role in optimal target volume definition.

Role of 18F-FDG - PET/CT in Patients with Differentiated Thyroid Cancer Who Present with Elevated Thyroglobulin and Negative 131I Whole Body Scan

Aim of the work: To detect the ability of 18F-FDG with PET/CT to explain the elevated Tg levels in patients with negative 131I whole body diagnostic dose scan and to correlate of 18F-FDG with PET/CT with other diagnostic methods and histopathologic diagnosis.Patients and methods: 20 patients (13 males and 7 females) with pathologicall proven differentiated cancer thyroid were included in the study. All patients were subjected to near total thyroidectomy. 8 out of the 20 patients also underwent lymph node dissection. All received 131I ablation and had a negative whole body scan during follow up. They had unexplained elevated (> 10 ng/ml or more) or rising serum Tg levels (5-10ng/ml). All patients were subjected to full history, clinical examination, Laboratory and radiological assessment as well as 18F-FDG PET/CT study.Results: Neck US detected 7 lesions in 6 patients, all of them confirmed to be positive by PET/CT and an additional 13 neck lesions were detected by PET/CT in 15 patients. CT chest detected 8 patients, 6 of them confirmed by PET/CT while 2 lung lesions were negative. Eight additional mediastinal lymph node metastases were detected by PET/CT. PET/CT showed positive findings in 19/20 patients. In the remaining no cause for the elevated Tg was found with PET/CT or other radiological methods. PET/CT directed the management in 14/20 patients either to surgery or to external radiotherapy with normalization of Tg level within weeks after treatment.Conclusion: 18F-FDG PET/CT is of undeniable clinical value in patients with negative 131I whole-body scan results who are suspected of having a metastatic thyroid disease. It is able to detect significantly additional tumor sites than US or CT procedures.

Mammography, Sonography and MRI for Detection and Characterization of Invasive Lobular Carcinoma of the Breast

Imaging of invasive lobular carcinoma (ILC) is more challenging than other types of breast cancer because of its spider web like growth pattern. Mammography has a relevant number of false negative exams, especially in dense breasts. Mammographic appearance of ILC is often subtle. Distinct mass like aspects are absent more often when compared with other types of breast cancer, and lesions are frequently only mildly opaque. Microcalcifications are uncommon. The addition of an ultrasound exam can improve rates of detection and diagnosis of ILC, but even when combining modalities ILC can be missed. If clinical signs are suspicious, magnetic resonance imaging (MRI) can help to detect ILC. MRI should also be considered in preoperative staging if treatment with breast conservation is favoured, particularly to assess maximal tumor dimensions. Mammographic findings do not correlate well with pathological tumor size. Additional tumor sites detected by MRI only should be validated cautiously, and guidelines established for multicentricity detected by mammography should not be used in the same way.

Radioimmunoguided surgery for recurrent colorectal cancer manifested by isolated CEA elevation

BACKGROUND Carcinoembryonic antigen (CEA) is a sensitive marker for detecting recurrent colorectal carcinoma. An asymptomatic rise of CEA can precede by several months the detection of recurrent cancer by standard imaging modalities. Yet, surgeons are hesitant to operate solely on the basis of an observed increase in CEA. We investigated the ability of radioimmunoguided surgery to enhance the surgeon's capability of detecting intraabdominal disease in these patients. METHODS Nineteen patients who underwent radioimmunoguided surgery for suspected tumor recurrence based solely on elevated CEA were included in the study. They underwent colonoscopy and CT of the abdomen and chest, all of which were negative. They then underwent scintigraphy scan with an anti-CEA monoclonal antibody (MoAb) labeled with 99mTc or Indium I-111. All patients were injected with the CC49 MoAb (an anti-TAG-72 tumor-associated glycoprotein) labeled with 125I three weeks before surgery. During surgery, traditional exploration was followed by survey with a gamma-detecting probe. RESULTS Traditional surgical exploration identified 26 recurrent tumors: 7 hepatic, 8 pelvic, 6 retroperitoneal, 3 colonic, 1 splenic, and 1 anastomotic. Radioimmunoguided surgical exploration confirmed all recurrent tumors and identified additional tumor sites in seven patients that resulted in changing the surgical plan. CEA scans correlated with intraabdominal findings in seven patients. Abdominal pathology did not correlate completely with the scans in three patients, and CEA scan results were undetermined in two patients. CONCLUSION Patients with elevated CEA and no other findings should be operated upon without delay, and radioimmunoguided surgery should be used to enhance the surgeon's knowledge of the extent of disease. Cancer 2000;89:1692–8. © 2000 American Cancer Society.

Arsenic: risk assessment for california drinking water standards

Six California counties contain 15 water systems with arsenic concentrations above the 50 ppb Maximum Contaminant Level (MCL). Arsenic compounds are carcinogenic in humans by oral and inhalation routes. They are also fetotoxic and teratogenic in mice, rats and hamsters and cause a variety of toxic effects in the gastro-intestinal tract, circulatory system, skin, liver, kidney, nervous system and heart. The US EPA has identified an oral human chronic No-Observable-Adverse-Effect Level (NOAEL) of 0.0008 mg/kg-d based on skin and vascular effects. In 1988 EPA estimated the human carcinogenic potency of arsenic in drinking water to be about 2 × 10 −1/μg/kg-d with a 10 −6 lifetime skin cancer risk equivalent to consumption of 21/day at 20 ppt. Recently Smith et al. (1990) estimated the potency of arsenic to be 5.3 × 10 −3μ/g/kg-d based on the same human data. Also Chen et al. (1988) and Chen and Wang (1990) identified the additional tumor sites of liver, lung, bladder, kidney, nasal cavity and prostate. The lifetime risk of developing skin cancer at the 50 ppb MCL level (21/day) is about 8 in 1000. Preliminary analysis of the recent data on other tumor sites indicate comparable risks of: females - lung, 11.0; bladder, 6.7; kidney, 3.4; liver, 0.3; males - lung, 6.1, bladder, 2.2; kidney, 1.4; liver, 0.2. On the basis of a skin cancer potency of 5.3 × 10 −3/μg/kg-d, a Recommended Public Health Level (RPHL) of 2 ppt (0.002 μg/l) is being proposed in accordance with the provisions of the Safe Drinking Water Act of 1989. This value assumes a body weight of 70 kg, a water consumption of 21/day, a relative source contribution of 20%, and a lifetime extra cancer risk of 10 −6.

Oxygen in Human Tumors: Correlations between Methods of Measurement and Response to Therapy: Summary of a Workshop Held November 19-20, 1992, at the National Cancer Institute, Bethesda, Maryland

Knowledge about the oxygenation of human tumors and its importance in the response to radiotherapy is crucial to the effort to develop improved treatment methods for radiotherapy. The measurement of oxygenation of human tumors and correlations with response to radiotherapy were the subjects of a recent workshop sponsored by the National Cancer Institute. The following methods for measuring oxygen or hypoxia, or a parameter related to either, were presented: polarographic oxygen electrodes, the comet and alkaline elution assays for radiation-induced DNA damage, nitroimidazole binding assays, hemoglobin saturation assays, magnetic resonance spectroscopy, electron spin resonance spectroscopy, phosphorescence imaging, and an assay for tumor interstitial pressure. The electron spin resonance, alkaline elution, and phosphorescence imaging methods have not been used in human tumors. The comet assay, nitroimidazole binding assays, magnetic resonance spectroscopy, cryospectroscopy, and near-infrared spectroscopy have been employed in human tumors, but correlations to treatment response have not been made. Polarographic measurements have indicated that the presence of hypoxia correlates with a poor response to radiotherapy in cervical cancers, but additional data are needed on early-stage disease, and with long-term follow-up on local control and survival. If these confirm the correlation between hypoxia and poor response to radiotherapy, additional tumor sites should be studied. Future clinical trials of treatments that sensitize, exploit, or kill hypoxic cells should identify and include the individual patients with hypoxic tumors. Fundamental unanswered questions regarding the assessment of tumor oxygenation concern the need for invasive procedures, the spatial resolution needed for prediction of response to radiotherapy, the importance of reoxygenation, differences between tumors in rates and degrees of reoxygenation, whether measurements made during a course of therapy are of value, and correlations among methods and with other predictive assays such as intrinsic radiosensitivity and potential doubling time.

Diagnosis and treatment of neuroblastoma using metaiodobenzylguanidine.

Neuroblastoma is a lethal and not uncommon tumor in childhood. Early detection and display of the spread of the tumor is highly desirable for proper treatment. Nine children suspected of having neuroblastomas were examined by I-131 metaiodobenzylguanidine (I-131 MIBG) imaging. In two recent studies I-123 metaiodobenzylguanidine (I-123 MIBG) was used. A primary adrenal neuroblastoma was correctly identified in three cases. In two patients additional tumor sites were found. In one patient, who was in complete remission, no pathologic accumulation of I-131 MIBG was found. I-131 MIBG images were also normal in four patients with other types of neoplastic diseases. A boy with multiple metastases was treated with 100 mCi of I-131 MIBG. He developed transient gastrointestinal illness and there was no regression of the tumor deposits. In one girl with a large adrenal neuroblastoma high uptake of I-131 MIBG was observed. She received two therapy doses of I-131 MIBG (35 mCi and 75 mCi) with curative intention giving a total absorbed dose in the tumor of approximately 76 Gy. In spite of high retention of radioactivity in the tumor, regression did not occur, but her general condition was improved. In the present study, images of superior quality were obtained with I-123 MIBG imaging. It is concluded that imaging using I-131 MIBG or I-123 MIBG should be used in both the initial evaluation and the follow-up of children with neuroblastoma.

Diagnosis and Treatment of Neuroblastoma Using 131 l-Meta-lodobenzylguanidine

Neuroblastoma is a lethal and not uncommon tumor in childhood. Early detection and display of the spread of the tumor is highly desirable for proper treatment. Nine children suspected of having neuroblastoma were examined by 131I-meta-iodobenzylguanidine (131I-MIBG) scintigraphy. In two recent studies 123I-meta-iodobenzylguanidine (123I-MIBG) was used. A primary adrenal neuroblastoma was correctly identified in 3 cases. In 2 patients additional tumor sites were found. In one patient, who was in complete remission, no pathological accumulation of 131I-MIBG was found. 131I-MIBG scintigraphies were also normal in 4 patients with other types of tumor. In one girl with a large adrenal neuroblastoma high uptake of 131I-MIBG was observed. She received two therapy doses of 131I-MIBG (1300-2800 MBq) with curative intention giving a total absorbed dose in the tumor of approximately 90 Gy. In spite of high retention of radioactivity in the tumor, regression did not appear, but her general condition was improved. In the present study images of superior quality were obtained by 123I-MIBG scintigraphy. It is concluded that scintigraphy with 131I- or 123I-MIBG should be used for primary visualization and control of neuroblastomas.